May 12, 2010 — In a joint meeting, the US Food and Drug Administration's Arthritis Advisory Committee and Drug Safety and Risk Management Advisory Committee today failed to endorse the approval of the novel anti-inflammatory drug naproxcinod for the relief of signs and symptoms of osteoarthritis, sending the drug's French sponsor back to the drawing board for additional safety and efficacy studies.
Only one of the 18 committee members voted in favor of approval. Sixteen voted no, and one, Kathleen O'Neil, MD, the committee chair, abstained.
The new drug application by NicOx, headquartered in Sophia Antipolis, France, had generated considerable buzz with the company touting naproxcinod — a first-in-class cyclooxygenase-inhibiting nitric oxide donator (CINOD) — as an anti-inflammatory agent that had good gastrointestinal tolerability and safety but did not raise blood pressure.
Naproxcinod is designed to release naproxen and a nitric oxide donating moiety. NicOx believes that these nitric oxide donating properties permit naproxcinod to mitigate the gastrointestinal effects and rise in blood pressure commonly seen with naproxen.
The panel liked the concept, but felt that the sponsor had not presented enough efficacy or safety data.
"All told, this is a drug that the panel would love to see more data on," said Dr. O'Neil in her summary. "The panel in general was enthusiastic about the potential for this drug but would like to see the potential become kinetic."
"I voted no, and to the sponsor, I'll say I vote an encouraging no," said Robert Harrington, MD, professor of medicine and director, Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina. "I actually like the concept of the drug. There is a lot to be hopeful about here that might actually offer a step forward in care. But I don't believe that the studies that have been presented meet the typical evidentiary standard that is required to be able to gain approval and get onto the market."
William O. Brackney, one of 2 patient representatives on the panel, urged NicOx to get its act together and "find a way to get this drug to market if it truly is as good as it portends to be."
Sidney Wolfe, MD, director of Health Research Group of Public Citizen, Washington, DC, voted no because he wasn't convinced that naproxcinod had any more benefit than the tried and true naproxen. Nor was he convinced about the company's claim that it reduces cardiovascular events.
"I think the idea of looking at its reduction of the harm that otherwise comes with naproxen is a good start, but we really need outcomes. We have had too much going on in terms of adverse cardiac outcomes with this family of drugs to just sort of blow that off," Dr. Wolfe explained.
"Naproxen is one of the more toxic gastrointestinal drugs and the theory that the company came with — that naproxcinod is going to relieve the GI toxicity — really needs to be studied further. So if we had the 2 safety outcomes with regard to cardiovascular and GI toxicity, as well as the efficacy outcomes, that would be fine, but we don't have any of them," he said.
Nancy Olson, MD, professor of internal medicine and McGee Foundation Chair in Arthritis Research at the University of Texas Southwestern Medical School, Dallas, said the reason she voted no was because she was not convinced by the blood pressure data the company presented.
"If I had been really convinced that there was a significant decrease in blood pressure that would have overridden some of the other concerns because that would have been an obvious benefit that nothing else out there offers," she said. "I would be less concerned about GI and long-term cardiovascular events. There needs to be more data. We need longer than 13 or 26 weeks."
The single committee member who voted yes said she had been convinced by the sponsor's data that naproxcinod has great potential. "I'm not worried about the safety because the molecule of naproxen is quite known and I didn't see any signal that would worry me that something bad was going to happen," said Maria Sjogren, MD, MPH, director, Hepatology Research, Walter Reed Army Medical Center, Washington, DC.
"I wish I could be so lucky that when I develop osteoarthritis and I have high blood pressure that my physician will be reading the literature and will try me on this drug and see how I do," Dr. Sjogren added. "I don't see a problem with that. I'm voting yes with full conscience of what this drug could do for patients in such a situation."
But David Blumenthal, MD, associate professor of medicine, Case Western Reserve University, Cleveland, Ohio, said that he wanted to see more safety data, because naproxcinod is a new molecule. "The company can't have it both ways. It says it is a new molecular entity and we should all be excited about its potential effects on blood pressure, but as far as the safety data goes, it gets a pass because it's so similar to naproxen. We don't have the full story on the safety effects of the nitric oxide releasing properties of this medicine unless you subject this patient population to the same safety studies that all other new molecular entitities are subjected to. So I personally am not willing to give the company a pass on that."
All panel members called for longer-term studies. As Dr. Harrington said, "I've heard all day from my rheumatology colleagues that the osteoarthritis population is a large population. If it is, we ought to be able to do a large trial. If you want to treat large numbers of patients you should study large numbers of patients and you should study them in a pragmatic way, addressing the populations at risk. If some 20 million people have the disease, we ought to be able to find a few thousand who would be willing to be in studies.
